HIV associated dementia (HAD) is a significant and potentially treatable cause of cognitive decline. Despite improved AIDS mortality rates with the advent of highly active anti-retroviral therapy (HAART), the prevalence of HAD is increasing. Neuropathological studies of brain tissue from patients with HAD and other neurodegenerative diseases such as Alzheimer's disease (AD), reveal evidence of prominent neuroinflammatory changes including activation of microglia, the resident brain immune cells. Mutations in the genes coding for the presenilin proteins (PS), presenilin 1 (PS1) and presenilin 2 (PS2) cause familial AD, and thus PS are a natural focus of study in neurodegenerative disease. PS are the catalytic component of the y-secretase complex, a membrane protease that processes amyloid peptide protein to form amyloid beta peptide, found in AD plaques. The PS y-secretase complex also cleaves numerous substrates such as ErbB4, Notch, p75 that have been implicated in inflammatory processes. Previous work suggests a role for PS in central nervous system inflammation and our preliminary data demonstrate that PS2 protein is increased in HAD brain as well as in microglia stimulated by the HIV coat protein, gp120. In this K08 career development proposal, we hypothesize that PS are integral to the neuroinflammatory processes in HAD. During the award period the investigator will study the effects of pharmacological y-secretase inhibition and shRNA knock down of PS in microglia activated by the HIV coat protein, gp120. Primary microglia from PS2 knockout mice will be assayed for gp120 induced activation. Using immunohistochemistry we will investigate cell type and sub-cellular expression in HAD brain of two Y-secretase substrates implicated in the microglia inflammatory response, ErbB4 and p75NTR. We will determine if the known y-secretase components assemble in microglia using co-immunoprecipitation and measure microglia y-secretase activity in response to inflammatory stimuli. PS are known to mediate cellular functions independent of the y-secretase complex, and therefore we will employ proteomic techniques to identify novel PS binding partners in quiescent and gp120 stimulated microglia. A multidisciplinary approach including mentored bench research, didactics, seminars and professional conferences will provide the necessary training environment to promote the development of this young investigator into an independent clinician-scientist. HAD is a costly burden to individuals, families and the health care system. This proposal will contribute to the fundamental understanding of mechanisms in HIV induced neuroinflammation that will potentially lead to more effective therapeutics in the treatment of HAD.